The human 5-hydroxytryptamine-6 (5-HT6) receptor, one of the most recently cloned serotonergic receptors, is a 440-amino acid polypeptide with seven transmembrane spanning domains typical of the G-protein-coupled receptors. It is one of the 14 receptors that mediate the effects of the neurotransmitter 5-hydroxytryptamine (5-HT, serotonin)(Hoyer et al, Neuropharmacology, 1997,36:419). Within the transmembrane region, the human 5-HT6 receptor shows about 30-40% homology to other human 5-HT receptors and is found to be positively coupled to adenylyl cyclase.
The prominent localization of 5-HT6 receptor mRNA in the nucleus accumbens, striatum, olfactory tubercle, substantia nigra, and hippocampus of the brain (Ward et al, Neuroscience, 1995, 64:1105) together with its high affinity for several therapeutically important antipsychotics and antidepressants, suggest a possible role for this receptor in the treatment of schizophrenia and depression. In fact, the prototypic atypical antipsychotic agent clozapine exhibits greater affinity for the 5-HT6 receptor than for any other receptor subtype (Monsma et al, J. Pharmacol. Exp. Ther., 1994, 268:1403).
Although the 5-HT6 receptor has a distinct pharmacological profile, in vivo investigation of receptor function has been hindered by the lack of selective agonists and antagonists. Recent experiments demonstrated that chronic intracerebroventricular treatment with an antisense oligonucleotide, directed at 5-HT6 receptor mRNA, elicited a behavioral syndrome in rats consisting of yawning, stretching, and chewing. This syndrome in the antisense-treated rats was dose-dependently antagonized by atropine (a muscarinic antagonist), implicating 5-HT6 receptor in the control of cholinergic neurotransmission. Therefore 5-HT6 receptor antagonists may be useful for the treatment of memory dysfunction (Bourson et al, J. Pharmacol. Exp. Ther., 1995, 274:173), and to treat other CNS disorders.
It is an object of the present invention to provide compounds having 5-HT6 receptor antagonist activity. It is a further object of the present invention to provide compounds that are selective and/or potent with respect to their binding at the 5-HT6 receptor.